Stabilized form of vitamin b6 and process of preparing the same



Patented Nov. 4, 1941 STATES STABILIZED FORM OF VITAMIN Be AND IROCESS F PREPARING THE SAW John V. Scudi, Astoria, Long Island, N. Y., as-' signor to Merck & 90., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Application November 6, 1940, SerialNo. 364,597

Claims. (onto-29v) tions'(pH 7.0-7.5) are unstable to' autoclaving,

and in the usual sterilization procedures, undergo a loss of activity, and also, precipitation of an insoluble material occurs.

Heating'a 10% neutral solution of vitamin Be at 125 C. and 20 lbs. pressure for 20 minutes causes the solution to become yellow in color, and

precipitation -of a relatively insoluble material takes place. Precipitation of an insoluble sub stance interferes seriously with the parenteral administration of such a solution. This insoluble material possesses considerably less activity than an equal weight of vitamin B6 when tested by curative assay methods.

The insoluble material results from the autocondensation of two or more molecules of vitamin B6. The rate at which the condensation product is formed varies with the vitamin concentration, the time of heating, and the temperature. lutions (1%), precipitation may not occur for several days, whereas uponautoclaving stronger solutions (10%), precipitation usually occurs within a few hours. i

I have discovered that a neutral aqueous solu-- tion of vitamin B6, which is stable to autoclaving, can be prepared by the addition of boric acid to an aqueous solution of a vitamin B6 salt, with For example, upon heating dilute so-- demonstrated by potentiometric titration of solutions containing the following proportions:

Millimoles Calculated Millimoles vitamin millimoles of complex .BGHCL of complex formed 0. 495 l. 00 0. 25 O. 24 H3 1'33 3'51 3'35 2: 00 1100 1:00 0:98 2. 50 1. U0 1. 0O 0. 99

. In all cases the vitamin is bound to boric acidin the ratio of two molecules to one, respectively.

' This complex, when tested in'the cure of rat i acrodynia, shows activity equal to an equivalentv weight of vitamin B6, and is not irritating when administered intramuscularly.

Solutions of the vitamin-borate complex do not exhibit any local toxicity. -No general toxicity can be noted, even when these solutions were fed to emaciated, deficient animals. In human beings, a therapeutic dose of vitamin B6 HCl is estimated to be approximately 100 mg. Only 20-30 mg. of boric acid are required to stabilize this amount of vitamin. Since boric acid is adin the body, the vitaminrBs-borate complex apsubsequent adjustment of the pH to about 7.0-7.5.

Such solution remains colorless, and does 'not precipitate upon autoclaving; The stabilization of the vitamin solution results from the forma-'- tion of a new borate complex having the following structure:

NJCHa CH3 N wherein M is a non-toxic metal, such as sodium,

potassium, calcium, magnesium, aluminum, e tc.,

and wherein n is an integer equal in value to the present, not all of the vitamin is bound in the complex. In the presence of an excess of boric acid, the excess acid remains unbound. This is ,pears to be eminently suitable for parenteral administration. i

The new compound ofthe present invention may be obtained by dissolvinglOO mg. of vitamin Bs hydrochloride and 25 mg. of boric acid in Water, and adjusting to a pH of about 7.0-7.5 by the'dropwise addition of dilute sodium hydroxide.

This solution can'be used as such, for example,

it can be autoclaved and then employed in in-' jection, or the vitamin Bs-borate complex can be recovered from a concentrated solution, and mayin the above complex, by'employing metal hydroxides other than sodium hydroxide.

I LN/CHJ GIIa N wherein M is a non-toxic metal, and wherein n is an integer equal in value to the valence of the metal.

noon

2. A substantially neutral aqueous solution of' the compound of the formula:

omo-B-o cm Hocn jo oficmon M 5 LN CH: CHx N wherein M is a non-toxic metal, and wherein n is an integer equal in value to the valence of' the 10 metal.

' 3. The compound of the formula:

cmo-n -ocm noon 4. The compound of the formula:

on,o-B -o c H,

5. The compound of the formula:

CHiO-B 0cm 6. A substantially neutral aqueous solution of the compound of the formula:

omo-B-oom nocn o 0 onion J Na on on N N '7. A substantially neutral aqueous solution of the compound of the formula: 7

KOCH O 0 CHaOH N CHI CH; N

8. A substantially neutral aqueous solution of the compound of the formula:

CH:O-B-OCH:

BOOK 0 O CHzOH I Cu N CH: CH: N 2

9. The process comprising dissolving a vitamin Ba salt and boric acid in an aqueous medium, and subsequently adjusting the pH of the solution to about 7.0-7.5.

10. The process comprising dissolving a vitamin B6 hydrochloride and boric acid in an aqueous medium, and subsequently adjusting the pH of the solution to about 7.0-7.5.

- JOHN V. SCUDI. 

